1,3-dimethyl-4,5-di(p-substituted phenyl)-6h-pyrrolo(2,3-c)pyrazoles

ABSTRACT

1,3-DIMETHYL-4,6-DI(P-SUBSTITUTED PHENYL)-6H-PYRROLO(2,3-C)PYRAZOLES AND NOVEL INTERMEDIATES USEFUL IN THEIR SYNTHESIS. THE COMPOUNDS ARE USEFUL AS ANTI-INFLAMMATORY AND ANTI-PYRETIC AGENTS.

United States Patent ABSTRACT OF THE DISCLOSURE 1,3 dimethyl 4,6 di(p-substituted phenyl)-6H-pyrrolo[2,3-c]pyrazoles and novel intermediates useful in their synthesis. The compounds are useful as anti-inflammatory and anti-pyretic agents.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel 1,3-dimethyl-4,5-di(psubstituted phenyl) 6H pyrrolo[2,3-c]pyrazoles repre' sented by formula omm wherein R is hydrogen, C -C alkyl, C -C alkoxy, or halo; and R is benzoyl, halo-substituted benzoyl, di(C C )alkylamino (C -C alkyl, 2-thiophenecarbonyl, hydrogen, or C -C alkyl.

The term C -C alkyl refers to straight and branched chain alkyls and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl.

The term C -C alkoxy includes methoxy, ethoxy, propoxy and butoxy.

The term halo as used herein includes chloro, iluoro, bromo and iodo.

The compounds of this invention are useful as antiinllammatory and anti-pyretic agents when administered to mammalian patients in dosages of from to 50 mg./ kg. of body weight daily, preferably in divided dosages (i.e., 175 to 875 mg. four times daily). The anti-inflammatory activity of the compounds was established in the carrageenan rat paw edema test (Winter et'al., Proc. Soc. Exp. Biol. Med. 111, 554 [1962].

The anti-pyretic activity was established by the yeastinduced fever test in rats.

The preferred method of preparing the compounds of this invention is represented by the following reaction scheme.

ice

(EH; H

4 (I) RIX I! l n i ('JH: R2

Compounds of the Formula 11 CH O=C- ---R1 117 l NJNH H-@Ri H (II) wherein R, is as defined herein above are novel compounds which are useful as intermediates in the synthesis of the final products I (4 and 5).

The following examples further illustrate the present invention.

EXAMPLE 1 5- [ot-(p-methoxybenzoyl)-p-methoxybenzylamino]-1,3- dimethylpyrazole hydrochloride A solution of p-anisoin (27.2 g., 0.10 mole), 1,3-dimethyl-S-aminopyrazole (12.2 g., 0.11 mole) and ptoluenesulfonic acid monohydrate (0.95 g., 0.005 mole) in benzene ml.) was refluxed under nitrogen atmosphere for 48 hours using a Barrett trap to collect the water formed (1 ml.). The reaction mixture was filtered and the filtrate was evaporated to dryness to yield an oil (37.8 g.). A part of this oil was dissolved in alcohol and treated with ethanolic picric acid. The picrate melted at 168-169.

Analysis.-Calcd. for CgqHggNsOm (percent): C, 54.54; H, 4.41; N, 14.14; 0, 26.92. Found (percent): C, 54.58; H, 4.50; N, 14.20; 0, 26.67.

The picrate was dissolved in methanol and treated with amberlite IRA 400 resin in the OH form (previously washed with methanol). The resin was filtered and the filtrate was evaporated to dryness. The oily residue was dissolved in ether and anhydrous hydrogen chloride was bubbled through the solution to give the hydrochloride salt, M.P. 230-32 (from alcohol).

Analysiscaled. for C H ClN 0 (percent): C, 62.76; H, 6.02; N, 10.46. Found (percent): C, 62.61; H, 6.06; N, 10.60.

EXAMPLE 2 S-[a-(p-chlorobenzoyl)-p-chlorobenzylamino]-1,3- dimethylpyrazole A solution of 4,4'-dichlorobenzoin 16.9 g., 0.06 mole), 1,3-dimethyl-5-aminopyrazole (7.3 g., 0.066 mole) and p-toluene-sulfonic acid monohydrate 0.57 g., 0.003 mole) in 80 ml. of benzene was refluxed for 12 hours under nitrogen atmosphere. The picrate was formed and converted to the free base as described in Example 1, to yield 7.6 g. of product, M.P. -142 (from alcohol).

Analysis.Calcd. for C H Cl- N O (percent): C, 60.97; H, 4.58; N, 11.23. Found (percent): C, 60.81; H, 4.01; N, 11.29.

3 EXAMPLE 3 5-[a-(p-methylbenzoyl)-p-methylbenzylamino]-1,3- dimethylpyrazole hydrochloride A solution of 4,4'-dimethylbenzoin (14.4 g., 0.060 mole), 1,3-dimethyl-S-aminopyrazole (7.3 g., 0.066 mole) and p-toluenesulfonic acid monohydrate (0.57 g., 0.003 mole) was refluxed in benzene (80 ml.) for 24 hours. The picrate was obtained as described in Example 1, M.P. 195197.

Analysis.Calcd. for C H H O (percent): C, 57.65; H, 4.66; N, 14.94. Found (percent): C, 57.68; H, 4.65; N, 14.92.

The picrate was converted to the free base and to the hydrochloride salt as described in Example 1, M.P. 223- 225.

EXAMPLE 4 1,3-dimethyl-4,5-dip-methoxyphenyl) -6H-pyrrolo- [2,3-c]pyrazole A stirred mixture of crude 5-[a-(p-methoxybenzoyD- p-methoxybenzylamino] 1,3 dimethylpyrazole (7.3 g., 0.02 mole), aniline (5.59 g., 0.06 mole) and aniline hydrobromide (1.7 g., 0.01 mole) was heated at 170 for 3 hours. The reaction mixture was evaporated to dryness under vacuum to remove the excess aniline. The viscous residue was dissolved in 100 ml. of methanol and treated with 50 ml. of amberlite IRA-400 resin in the OH form (previously washed with methanol). The resin was removed by filtration. The filtrate was evaporated to dryness to yield an oil which was treated wtih 200 ml. of ether. The insoluble pyrrolo[2,3-c]pyrazole was filtered. Yield 2.5 g. (35%), M.P.-230-232.

Analysis-Called. for C H N 0, (percent): C, 72.60; H, 6.09; .N, 12.10; 0, 9.21. Found (percent): C, 72.42; H, 6.14; N, 12.04; 0, 9.03.

EXAMPLE 5 1,3-dimethyl-4,5-di- (p-chlorophenyl)-6H-pyrrolo [2,3-cpyrazole] A stirred mixture of crude S-[a-(p-chlorobenzoyl)-pchlorobenzylamino]-1,3-dimethylpyrazole (24.8 g., 0.066 mole), aniline (18.4 g., 0.198 mole) and aniline hydrobromide (5.7 g., 0.033 mole) was heated at 170 for 1% hours. The reaction mixture was evaporated to dryness to yield an oil. Treatment with amberlite IRA-400 in the H form, filtration and evaporation to dryness gave a residue which was treated with petroleum-ether (B.P. 90-120") (some tar remained insoluble). The petroleum-ether extracts were cooled and the solid formed was filtered. Yield 8.4 g., M.P. 190195 C. The crude solid was treated with water, filtered and crystallized from alcohol, M.P. 226-228".

Analysis.Calcd. for C H Cl N (percent): C, 64.06; H, 4.24; N, 11.79. Found (percent): C, 64.10; H, 4.33; N, 11.64.

EXAMPLE 6 1,3-dimethyl-4,5-di-(p-tolyl)-6H-pyrrolo[2,3-c] pyrazole A stirred mixture of crude S-Ie-(p-methylbenzoyl)-pmethyl-benzylamino] 1,3 dimethylpyrazole (19.4 g., 0.058 mole), aniline (16.2 g., 0.174 mole) and aniline hydrobromide (5.1 g., 0.029 mole) was heated at 170 for 3 hours. The product was isolated as described in Example 4. Yield .5.5 g., M.P. 238240 (from alcohol).

Analysis.Calcd. for C H N (percent): C, 79.97; H, 6.71; O, 13.32. Found (percent): C, 79.71; H, 6.77; O, 13.35.

EXAMPLE 7 1,3-dimethyl4,5-diphenyl-6H-pyrrolo [2,3-c1pyrazole A solution of benzoin (21.23 g., 0.10 mole), 1,3-dimethyl-S-aminopyrazole (12.2 g., 0.10 mole) and p-tolu enesulfonic acid monohydrate (0.95 g., 0.005 mole) in ml. of benzene was refluxed for 14 hours under nitrogen atmosphere (1.6 ml. of water was collected). The reaction mixture was evaporated to dryness to yield an oil.

A part of the crude oil (12.22 g., 0.04 mole) was heated with aniline (11.8 g., 0.12 mole) and aniline hydrobromide (3.42 g., 0.02 mole) at for 3 hours. The product was isolated as described in Example 4, except that the residual oil Was dissolved in a minimum of alcohol and let stand. Yield 4.0 g. (35%), M.P. 130, solidified and melted at 210-211.

Analysis.--Calculated for C H N (percent): C, 79.41; H, 5.97; N, 14.62. Found (percent): C, 79.35; H, 5.96; N, 14.44.

EXAMPLE 8 1,3,6-trimethyl-4,S-diphenylpyrrolo [2,3-c] pyrazole To a stirred solution of 1,3-dimethyl-4,5-diphenyl-6H- pyrrolo[2,3-c]pyrazole (1.44 g., 0.005 mole) in 24 ml. of N,N-dime thylformamide was added sodium hydride (0.23 g., 0.005 mole). The reaction mixture was stirred for 1 hour at 25. Methyl iodide (0.71 g., 0.005 mole) dissolved in 10 ml. of N,N-dimethylformamide was added dropwise. After the addition was over, the stirring was continued for 17 hours at room temperature. Evaporation of the solvent yielded a solid which was crystallized from alcohol, 0.6 g. (40%), M.P. 176-177.

Analysis.--Calculated for C H N (percent): C, 79.70; H, 6.35; N, 13.94. Found (percent): C, 79.62; H, 6.58; N, 13.74. 1

EXAMPLE 9 1, 3-dimethy1-4,5-diphenyl-6- (p-chlorobenzoyl) -pyrrolo [2,3-c] pyrazole The reaction of 1,3-dimethyl-4,5-diphenyl-6H-pyrrolo [2,3-c]pyrazole (1.44 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and p-chlorobenzoyl chloride (0.88 g., 0.005 mole) in N,N-dimethylformamide (20 1111.), as described in Example 8 yielded 1.5 g. (70%) of product, M.P. 168-169". The analytical sample melted at 170- 171 (from alcohol).

Analysis.-Calculated for C H ClN O (percent): C, 73.32; H, 4.73; N, 9.86. Found (percent): C, 73.21, H, 4.67; N, 9.90.

EXAMPLE 10 1,3,6-trimethyl-4,5-di- (p-methoxyphenyl) -pyrrolo [2,3-c] pyrazole The reaction of 1,3-dimethyl-4,5-di-(p-methoxyphenyD- 6H-pyrrolo[2,3-c]pyrazole (3.5 g., 0.01 mole), sodium hydride (0.46 g., 0.01 mole) and methyl iodide (1.4 g., 0.01 mole) in N,N-dimethylformamide, as described in Example 8, gave 2.7 g., (75%) of product, M.P. 179-181. The analytical sample melted at 180-182" (from alcohol).

Analysis.Calculated for C H N O (percent): C, 73.11; H, 6.41; N, 11.63. Found (percent): C, 72.89; H, 6.51; N, 11.73.

EXAMPLE 11 1,3-dimethy1-4,5-di(p-methoxyphenyl)-6-benzoylpyrrolo [2,3-c] pyrazole The reaction of 1,3-dimethyl-4,5-di(p-methoxyphenyl)- 6-H-pyrrolo[2,3-c]pyrazole (1.74 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and benzoyl chloride (0.71 g., 0.005 mole) in 20 ml. of N,N-dimethylformamide, as described in Example 8, yielded 1.5 g., (66% M.P. 146 150". The analytical sample melted at 162163.

Analysis.--Calculated for C H N O (percent): C, 74.48; H, 5.58; N, 9.31; O, 10.63. Found (percent): C, 74.28; H, 5.69; N, 9.24; O, 10.70.

EXAMPLE 12 1,3-dimethyl-4,5-di- (p-methoxyphenyl)-6-(p-chlorobenzoyl pyrrolo [2,3-c1pyrazole The reaction of 1,3-dimethyl-4,5-di- (p-methoxyphenyl)- 6H-pyrrolo[2,3-c]pyrazole (3.47 g., 0.01 mole), sodium hydride (0.46 g., 0.01 mole) and p-chlorobenzoyl chloride (1.75 g., 0.01 mole) in 30 ml. of N,N-dimethylformamide, as described in Example 8, gave 2.7 g. (56%) of product, M.P. 176-178. The analytical sample melted at 178-179.

Analysis.Calculated for C H ClN O (percent): C, 69.20; H, 4.98; Cl, 7.30; N, 8.65; O, 9.88. Found (percent): C, 69.34; H, 4.98; Cl, 7.52; N, 8.82; O, 10.17.

EXAMPLE l3 1,3,6-trimethyl-4,5-di- (p-tolyl) -pyrrolo [2,3-c] pyrazole The reaction of 1,3 dirnethyl 4,5-di-(p-tolyl)-6H- pyrrolo[2,3-c]pyrazole (1.6 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and methyl iodide (0.71 g., 0.005 mole) in 25 ml. of N,N-dimethylformamide as described in Example 8 yielded 0.7 g. (44%) of product, M.P. 182-184.

Analysis.Calculated for C H N '(percent): C, 80.21; H, 7.04; N, 12.75. Found (percent): C, 80.40; H, 7.18; N, 12.78.

EXAMPLE 14 1,3-dimethyl-4,5-di-(p-tolyl)-6-benzoylpyrrolo [2,3-c]

pyrazole The reaction of 1,3 dimethyl-4,5-di-(p-tolyl)-6H-pyrrolo[2,3-c]pyrazole (1.6 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and benzoyl chloride (0.71 g., 0.005 mole) in 25 ml. of N,N-dimethylformamide as described in Example 8 yielded 0.4 g. (19%) of product, M.P. 198-200".

Analysis-Calculated for C H N O (percent): C, 80.16; H, 6.01; N, 10.02. Found (percent): C, 80.26; H, 6.16; N, 9.96.

EXAMPLE 15 1,3-dimethyl-4,5-di- (p-tolyl -6- (p-chlorobenzoyl) pyrrolo [2,3-pyrazole] The reaction in 1,3 dimethyl-4,5-di-(p-tolyl)-6H-pyrrolo[2,3-c]pyrazole (1.6 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and p-chlorobenzoyl chloride (0.88 g., 0.005 mole) in 25 m1. of N,N-dimethylformamide gave 0.4 g., of product (17%), M.P. 204206.

Analysis.-Calculated for C H ClN 0 (percent): C, 74.08; H, 5.33; N, 9.26. Found (percent): C, 74.20; H, 5.42; N, 9.29.

EXAMPLE 16 1,3, 6-trimethyl-4,5-dip-chlorophenyl) -pyrrolo [2,3-c] pyrazole The reaction of 1,3-dimethyl-4,5-di-(p-chlorophenyl)- 6H-pyrrolo[2,3-c]pyrazole (1.4 g., 0.0039 mole), sodium hydride (0.18 g., 0.0039 mole) and methyl iodide (0.55 g., 0.0039 mole) in ml. of N,N-dimethylformamide gave the product (0.7 g.) in 49% yield, M.P. 208-210.

Analysis.Calculated for o l-1 ,01,81 (percent): C, 64.87; H, 4.63; N, 11.35. Found (percent): C, 64.99; H, 4.68; N, 11.42.

EXAMPLE 17 1,3-dimethyl-4,5-di-(p-chlorophenyl) 6-benzoylpyrrolo [2,3-c]pyrazo1e The reaction of 1,3-dimethyl-4,5-di-(p-chlorophenyl)- fiH-pyrrolo[2,3-c1pyrazole (1.8 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and benzoyl chloride (0.71 g., 0.005 mole) in ml., of N,N-dimethylformamide yielded 0.93 g. (40%) of the desired product, M.P. 18'8- 190.

Analysis.-Calculated for C H Cl N 0 (percent): C,

6 67,83; H, 4.16; N, 9.13. Found (percent): 68.08; H, 4.24; N, 9.21.

EXAMPLE 18 1,3-dimethyl-4,5-di-(p-chlorophenyl)-6-(p-chlorobenzoyl) )-pyrrolo [2,3-c1pyrazole The reaction of 1,3-dimethyl-4,5-di-(p-chlorophenyl)- 6H-pyrrolo[2,3-c]pyrazole 1.8 g., 0.005 mole), sodium hydride (0.23 g., 0.005 mole) and p-chlorobenzoyl chloride (0.88 g., 0.005 mole) in 25 ml. of N,N-dimethylformamide as describedin Example 8 gave the expected product in 32% yield (0.8 g.), M.P. 186-188".

Analysis.-Calculated for C H Cl N O (percent): C, 63.11; H, 3.67; N, 8.49. Found (percent): 63.31; H, 3.72; N, 8.66.

EXAMPLE 19 l ,3 -dimethyl-4,5- dip-methoxyphenyl -6-N,N-diethylaminoethyl pyrrolo[2,3-c]pyrazole To a stirred solution of 1,3-dimethyl-4,5-di-(p-methoxyphenyl)-6H-pyrrolo[2,3-c]pyrazole (3.5 g., 0.01 mole) in 25 ml. of N,N-dimethylformamide was added sodium hydride (0.46 g., 0.01 mole). The reaction mixture was stirred for 2 hours at 25. Diethylaminoethyl chloride (1.4 g., 0.01 mole) dissolved in 25 m1. of N,N-dimethylformamide was added dropwise. After the addition was over, the stirring was continued for 20 hours at room temperature. Evaporation of the solvent yielded an oil. Extraction with (high boiling) petroleum-ether and evaporation of the petroleum-ether layer yielded a crude solid. Crystallization with petroleum-ether yielded 1.7 g. (37%) of product, M.P. 108-l10.

Analysis.-Calculated for C H N 0, (percent): C, 72.62; H, 7.67; N, 12.55. Found (percent): C, 72.61; H, 7.87; N, 12.55.

EXAMPLE 20 1,3-dimethyl-4,5-di-(p-methoxyphenyl)-6-(2-thiophenecarbonyl) pyrrolo[2,3-c] pyrazole To a stirred solution of 1,3-dimethyl-4,5-di-(p-methoxyphenyl) 6H pyrrolo[2,3-c]pyrazole (3.6 g., 0.01 mole) in 25 ml. of N,N-dimethylformamide was added sodium hydride (0.46 g., 0.01 mole). The reaction mixture Was stirred overnight at room temperature. 2-thiophenecarbonyl chloride (1.5 g., 0.01 mole) in 25 ml, of N,N-dimethylformamide was added dropwise. After the addition was over, the stirring was continued for 2 hours. Evaporation of the solvent yielded an oil. A solid (crude) formed when the oil was treated with dry ether. Crystallization of the solid with alcohol yielded 1.4 g. (31%) of product, M.P. ISO-182.

Analysis.Calculated for C H N O S (percent): C, 68.25; H, 5.07; N, 9.18. Found (percent): C, 68.41; H, 5.26; N, 9.32.

The compounds of the present invention can be incorporated into various pharmaceutically acceptable dosage forms such as tablets, capsules, pills, suspensions and the like for immediate or sustained release, by combining them with suitable carriers or diluents according to methods well known in the art. In addition to the active agent and the pharmaceutically acceptable carrier or diluent, the dosage forms may additionally include various excipients, binders, fillers, lubricating agents, flavoring and sweetening agents and the like. However, in the case of for example, filled capsules, the compound can be the sole ingredient.

We claim:

1. A compound of the formula C EhwQ-Rl wherein R is hydrogen, alkyl of 1 to :4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halo; and R is benzoyl, halo-substituted benzoyl, dialkylominoalkyl in which each alkyl moiety is of 1 to 4 carbon atoms, Z-thiophenecarbony], hydrogen or alkyl of C -C carbon atoms.

2. A compound in accordance with claim 1 wherein R is hydrogen and R is alkyl of 1 to 4 carbon atoms.

3. A compound in accordance with claim 1: 1,3-dimethyl 4,5 di-(p-rnethoxyphenyl)-6H-pyrrolo[2,3-c] pyrazole.

4. A compound in accordance with claim 1: 1,3-dimethyl 4,5 di (p-chlorophenyl)-6H-pyrrolo[2,3-c] pyrazole.

5. A compoundin accordance with claim 1: 1,3-dimethyl 4,5 di (p-tolyl)-6H-pyrrolo[2,3-c]pyrazole.

6. A compound in accordance with claim 1: 1,3-dimethyl-4,5-diphenyl-GH-pyrrolo[2,3-c]pyrazo1e.

7. A compound in accordance with claim 1: 1,3,6-trimethyl-4,5-di- (p-methoxyphenyl) -pyrrolo [2,3 -c] pyrazole.

8. A compound in accordance with claim 1: 1,3,6-trimethyl-4,S-diphenylpyrrolo[2,3-c1pyrazole.

9. A compound in accordance with claim 1: 1,3,6-trimethyl-4,5-di-(p-tolyl)-pyrrolo[2,3-c]pyrazole.

10. A compound in accordance with claim 1: 1,3,6-trimethyl-4,S-di-(p-chlorophenyi)-pyrro1o[2,3-c]pyrazole.

11. A compound in accordance with claim 1: 1,3-dimethy1-4,5-di-( p-methoxyphenyl) 6 N,N-diethylamino ethyl pyrrolo[2,3-c]pyrazole.

References Cited FOREIGN PATENTS 168,299 2/1965 USSR 260-310 R OTHER REFERENCES NATALIE TROUSOF, Primary Examiner U.S. Cl. X.R. 

